Base de datos multicéntrica de hemorragia subaracnoidea espontánea del Grupo de Trabajo de Patología Vascular de la Sociedad Española de Neurocirugía: presentación,criterios de inclusión y desarrollo de una base de datos en internet = Spontaneous Subarachnoid Haemorrhage multicenter database from the Group for the Study of Vascular Pathology of the Spanish Society for Neurosurgery: Presentation, inclusion criteria and development of an internet-based registry

Introducción. La hemorragia subaracnoidea (HSA) continúa siendo una de las enfermedades de interés neuroquirúrgico de más alta morbilidad y mortalidad. Su estudio es clave a la hora de mejorar la atención de estos enfermos en nuestro medio. Con este fin el Grupo de Trabajo de Patología Vascular de la SENEC decidió la creación de una base de datos multicéntrica para su estudio. Material y métodos. Se incluyen en esta base de datos todos los casos de hemorragia subaracnoidea espontánea ingresados en los centros participantes de forma prospectiva desde Noviembre del año 2004 hasta Noviembre del 2007. Se decidieron de forma consensuada los campos a recoger incluyendo edad, antecedentes personales, características clínicas, características radiológicas y del aneurisma, tipo de tratamiento y complicaciones de la enfermedad, evolución según la escala de evolución de Glasgow (GOS) al alta y a los seis meses así como el resultado angiográfico del tratamiento. Todos los campos se recogieron en un formulario rellenable a través de una página web segura. Resultados. En los tres años en los que ha estado activa la base se han recogido un total de 1149 casos de HSA espontánea recogidos por 14 centros participantes. Se ha estimado que es necesario aproximadamente un tiempo de 3.4 minutos para rellenar cada caso. En cuanto a sus características generales la serie es similar a otras series hospitalarias no seleccionadas. La edad media de los enfermos incluidos es de unos 55 años y la relación mujer:hombre 4:3. En cuanto a la gravedad del sagrado inicial un 32% de los enfermos se encontraba en mal grado clínico (WFNS = 4 ó 5). El 5% de los pacientes fallecieron antes de realizarse una angiografía que confirmara el origen aneurismático del sangrado. Se confirmó el origen aneurismático en el 76% de los pacientes mientras que en el 19% no se encontró ninguna lesión vascular responsable del sangrado, siendo clasificados como HSA idiopática. En los pacientes en los que se detectó un aneurisma su tratamiento fue endovascular en el 47% de los casos, quirúrgico en el 39, mixto en el 3% y no recibieron tratamiento de su aneurisma el 11% de los pacientes por fallecimiento precoz. En cuanto a su evolución, la mortalidad global de la serie se sitúa en el 22%. Sólo el 40% de los enfermos con HSA aneurismática presentaron una buena evolución (GOS=5). Conclusiones. La HSA espontánea continúa siendo una enfermedad con alta morbilidad y mortalidad. Esta base de datos puede ser un instrumento para conocer mejor sus características en nuestro medio y mejorar sus resultados, ya que se trata de una serie multicéntrica hospitalaria no seleccionada. Sería pues recomendable que esta base constituyera el germen de un registro nacional de HSA espontánea. Introduction. Subarachnoid haemorrhage is one of the most severe neurosurgical diseases. Its study is crucial for improving the care of these patients in our environment. With this goal the Group for the Study of Neurovascular Pathology of the Spanish Society for Neurosurgery (SENEC) decided to create a multicenter registry for the study of this disease. Materials and methods. In this database we have prospectively included all cases with spontaneous subarachnoid haemorrhage admitted to the participant hospitals from November 2004 to November 2007. The fields to be included in the database were selected by consensus, including age, past medical history, clinical characteristics at admission, radiological characteristics including presence or absence of an aneurysm and its size and location, type and complications of the aneurysm treatment, outcome assessed by the Glasgow Outcome Scale (GOS) at discharge and six months after the bleeding as well as the angiographic result of the aneurysm treatment. All fields were collected by means of an electronic form posted in secure web page. Results. During the three years of study a total of 1149 patients have been included by 14 Hospitals. The time needed to fill in a patient in the registry is approximately 3.4 minutes. This series of patients with spontaneous SAH is similar to other non-selected in-hospital series of SAH. The mean age of the patients is 55 years and there is a 4:3 female to male ratio. In relation to the severity of the bleeding 32% of the patients were in poor clinical grade at admission (WFNS 4 or 5). 5% of the patients died before angiography could be performed. An aneurysm was confirmed as the origin of the bleeding in 76% of the patients (aSAH), while in 19% of the patients no lesion was found in the angiographic studies and were thus classified as idiopathic subarachnoid hemorrhage (ISAH). Of those patients with aSAH, 47% were treated endovascularly, 39% surgically, 3% received a combined treatment and 11% did not receive any treatment for their aneurysm because of early death. Regarding outcome, there is a 22% mortality in the series. Only 40% of the patients with aSAH reached a good outcome at discharge (GOS = 5). Conclusions. Spontaneous SAH continues to be a disease with high morbidity and mortality. This database can be an ideal instrument for improving the knowledge about this disease in our environment and to achieve better results. It would be desirable that this database could in the future be the origin of a national registry of spontaneous SAH

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for druginduced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A* 33: 01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9 - 3.8; P = 2.4 x 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6 - 2.5; P = 9.7 x 10(-9)). The association with A* 33: 01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A* 33: 01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6 - 2.7; P = 4.8 x 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0 - 9.5; P = 7.1 x 10(-9)). We validated the association between A* 33: 01 terbinafine-and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A* 33: 01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.Peer reviewe

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

Journal Article;BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.Supported by a research grant (Fondo de Investigación Sanitaria, PI12-00620), the Agencia Española del Medicamento, and the Innovative Medicines Initiative Safer and Faster Evidence-based Translation consortium (Framework Programme for Research and Technological Development (FP-7) grant agreement number 523 705, IMI-2008-T5). CIBERehd is funded by the Instituto de Salud Carlos III.Ye